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Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

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Abstract

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D2 dopamine receptors. N-methyl-d-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D2 dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.

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Acknowledgments

Dr Abel Lajtha emigrated from Hungary a few years after the Second World War. In the following years, he became the Director of Center for Neurochemistry at Wards Island, New York, NY and several Hungarian scientists had the chance to visit his laboratory. Scientists, who worked with Dr Lajtha, could always count on his support and patience, not only when they worked with him directly, but also later in their career. Of the authors of this paper, KN, ZsJ, and LGH spent shorter or longer times working with Dr Lajtha and his coworkers; many times in projects that later proved to be pioneering thoughts in neurochemistry. We would like to express our sincere gratitude to Dr Abel Lajtha for his mentorship and guidance in neurochemical research, and as Editor-in-Chief of Neurochemical Research.

This research was supported in part by the Research Council for Health Sciences, Hungarian Ministry of Health and Welfare (ETT-031/2009).

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  1. Gyorgy Levay

    Present address: Chemical Works of Gedeon Richter Plc, Budapest, Hungary

Authors and Affiliations

  1. Division of Preclinical Research, EGIS Pharmaceuticals Plc, Budapest, Hungary

    Katalin Nagy, Bernadett Marko, Katalin Pallagi, Geza Szabo & Zsolt Juranyi

  2. Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

    Gabriella Zsilla

  3. Department of Organic Chemistry, Semmelweis University, Budapest, Hungary

    Peter Matyus

  4. Division of Chemical Research, EGIS Pharmaceuticals Plc, Budapest, Hungary

    Jozsef Barkoczy

  5. Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad ter 4, 1089, Budapest, Hungary

    Laszlo G. Harsing Jr.

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Special issue article in honor of Dr. Abel Lajtha.

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Nagy, K., Marko, B., Zsilla, G. et al. Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone. Neurochem Res 35, 2096–2106 (2010). https://doi.org/10.1007/s11064-010-0241-0

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